1. Field of the Invention
The present invention relates to a method for administering autologous stem cells in premature infants and, more particularly, to a method for intrathecal administration of autologous cord blood derived stem cells in premature infants sustaining intraventricular hemorrhages.
2. Description of the Related Art
Despite advances in the science of neonatal care and support of younger gestational age infants, these infants are at increasingly greater post-natal risks associated with their physiologic prematurity. It is well recognized that the incidence of peri- and intra-ventricular hemorrhage (IVH) is inversely proportional to gestational age. Although the incidence of hemorrhages in very low birth weight infants (<1500 grams) or in those less than 34 weeks gestation has been reported to be as great as 50 percent, the actual incidence in recent years has greatly improved to somewhere between 10 and 20 percent (although no firm data with regards to actual numbers or severity can be estimated). Improvements in and the availability of perinatal and postnatal care of these infants, as well as the use of indomethacin have contributed to the significant benefits recognized. However, it has been suggested that the actual number of premature infants who survive following an intraventricular hemorrhage is increasing since greater than 85% of infants between 700-1500 grams now survive. The risk of death and/or short term and long term complications to these premature infants, however, still exists.
Over 90 percent of intraventricular hemorrhages in premature infants occur within the first 72 hours of life, are most likely associated with physiologic changes within the premature neuro-circulation of the subependymal germinal matrix, as well as the potential contributing roles of abnormalities in primary and secondary hemostasis and other metabolic stress factors such as acidosis, oxygenation (hypoxia), intravascular nitric oxide and hydrogen sulfide levels and free oxygen radical formation. The initial signs and symptoms of an intraventricular hemorrhage are readily recognized by those routinely caring for the premature and include: apnea and hypoventilation, bradycardia, anemia, seizures, decreased muscle tone and activity, and a bulging anterior fontanel.
The diagnosis of an intraventricular hemorrhage is initially confirmed by a cranial ultrasound, usually performed in a serial manner to determine the extent, grade and progression of the hemorrhage (grades I-IV, as discussed infra). Alternative diagnostic considerations include the presence of sepsis, a pneumothorax (ventilated premature infant), cardiac disease, seizure activity, and/or metabolic and electrolyte disturbances.
Intracranial hemorrhages are classified into four grades, I-IV (as should be appreciated by those skilled in the art). These grades are defined by the severity of the hemorrhage as follows: Grade I—Hemorrhage limited to the subependymal matrix; Grade II—Hemorrhage extending into the ventricular system (<50%) without acute ventriculomegaly; Grade III—Hemorrhage extending into the ventricular system with acute dilatation due to “flooding” of 50% or more of one or both of the lateral ventricles; and Grade IV—Hemorrhage of grades I, II or III with extension into the brain parenchyma.
Although most hemorrhages are mild in nature, described as either grades I or II, and are associated with mild sequelae; hemorrhages of grades III and IV typically result in primary and secondary damage to the brain parenchyma and are associated with significant short term (e.g., post-hemorrhagic hydrocephalus) and long term complications (Grade III/IV sequelae include: hydrocephalus frequently requiring shunting, seizures, developmental delay and mental retardation, porencephalic cyst formation and cerebral palsy). The pathogenesis of a Grade III/IV hemorrhage seems to differ significantly from the other lesser grades, appearing to result from hemorrhagic venous infarctions surrounding the terminal vein and feeder vessels, most likely related to increased venous pressure following or associated with the development of a lower grade hemorrhage. In most cases the medical management of hydrocephalus is necessary and a severe hemorrhage imparts significant co-morbid effects on the general care of the infant, involving their cardio-respiratory management and seizure control. The parenchymal damage caused by a Grade III/IV intracranial hemorrhage results in tissue necrosis and non-neuronal cyst formation. Non-neuronal cysts can evolve to become contiguous with adjacent ventricles leading to the formation of a porencephalic cyst (see FIG. 1). Such conditions can result in the secondary neurologic diagnosis of cerebral palsy, with or without mental retardation and seizures (as noted supra).
It should be noted that the structural damage of a severe hemorrhage, Grade III/IV hemorrhages, commonly affect the integrity and cellularity of the germinal matrix. The germinal matrix is the primary location of glial cell precursors (neuroblasts & glioblasts). Glial cell precursors have demonstrated to have proliferative potential following stroke or brain injury in adults. These precursors have also demonstrated stem cell plasticity and multipotential characteristics, including their ability to differentiate into hematopoietic stem cells.
Conventional methods of prevention of intraventricular hemorrhages and severity mitigation include indentifying at-risk infants, minimizing contributing factors, early identification, and pharmaco-protectants such as antioxidants, and COX inhibitors. Supportive therapy for the post-IVH child includes seizure control, shunt care and maintenance, developmental therapy, sensory deficit care, special education, and lifelong support, each of which can cause financial and social burdens and psychosocial issues.